The present proposal will investigate the role of mitochondrial dysfunction and oxidative damage in several transgenic mouse models of neurodegenerative diseases. In particular we will investigate whether mice with a deficiency in dihydrolipoamide dehydrogenase will show increased oxidative damage, increased vulnerability to mitochondrial toxins and when crossed to transgenic mouse models of Alzheimer's disease (AD), Huntington's disease (HD), spinocerebellar ataxia1 (sca1) and dentatorubropallidoluysian atrophy (DRPLA) whether this will accelerate the phenotype. The mice with a deficiency of murine dihydrolipoamide dehydrogenase show deficiencies in several mitochondrial enzymes including a 50% deficiency in both pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. They will therefore help to test the potential role of reduced levels of these enzymes in neurodegenerative diseases. We will also carry out studies of mitochondrial oxygen utilization, oxidative damage and of the mitochondrial permeability transition in transgenic mouse models of HD, SCA1 and DRPLA. Another theme of the present program project grant is that increased transglutaminase activity may contribute to neuronal dysfunction and the development of cytoplasmic and nuclear inclusions in transgenic mouse models of HD, SCA1 and DRPLA. We will therefore measure brain transglutaminase activity as well as epsilon(4-glutamyl) lysine in brains of transgenic mouse models of these illnesses in collaboration with project 4. We will also test whether tissue transglutaminase inhibitors can extend survival and block the development of the intranuclear inclusions. We will also investigate whether transgenic mice with mutations in the amyloid precursor protein exhibit metabolic abnormalities in oxidative damage. Lastly if oxidative damage plays a role in the pathogenesis of neurodegenerative diseases then crossing transgenic ADP, HD, SCA1 or DRPLA mice with transgenic mice deficient in manganese SOD or glutathione peroxidase should accelerate the phenotype. We will therefore look at defects on survival as well as on markers of oxidative damage in mice following these crosses. The proposed studies will help to elucidate the role of mitochondrial dysfunction in transgenic mouse models of both AD as well as HD, SCA1 and DRPLA. They may also lead to novel and useful treatment strategies for these disorders.